The peptidyl prolyl cis-trans isomerase activity of cellular cyclophilins is essential for efficient hepatitis C virus (HCV) replication in hepatocytes. A large body of data, including clinical evidence, supports the idea that compounds that inhibit cyclophilin activity will be useful medicines for the treatment of HCV. These medicines may function by interacting with the NS5A and NS5B viral proteins and inhibiting proper assembly and function of the viral replication complex. Recently, published data has also suggested that some cyclophilin inhibitors may exert an antiviral effect by inhibiting cellular lipid trafficking or increasing the production of endogenous interferons.
The most studied class of cyclophilin inhibitors are structurally related to the immunosuppressant cyclosporine A (CsA). Since the discovery of CsA, several analogs have been identified that potently bind and inhibit cyclophilins but lack the ability of CsA to cause immunosuppression by binding calcineurin. In particular, CsA derivatives such as Debio025 and Scy-635 are non-immunosuppressive analogs of CsA that have been shown to reduce viral replication when administered HCV-infected patients.
Despite the efficacy of these agents, there is still a need for the identification and development of new cyclophilin inhibitors for the treatment of HCV and other diseases. Deb025, for example, has been reported to cause hyperbilirubinemia as a consequence of its ability to inhibit a variety of hepatic transporters. Inhibition of hepatic transporters is also a possible cause of undesirable drug-drug interactions.